REPLAY · Analysing the role of history, chance and selection on the evolution of plasmid-mediated antibiotic resistance
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2020-09-01 → 2022-10-31
- EU contribution
- €172,932
- Participants
- 1
- Scheme
- MSCA-IF
Lines connect the coordinator with its partners.
Results in brief
Analysing the role of history, chance and selection on the evolution of plasmid-mediated antibiotic resistance
What is the problem addressed by REPLAY? Antibiotic resistance (AMR) in bacteria is one of the major health problems facing modern medicine. AMR can emerge by de novo mutations or by horizontal gene transfer (HGT) events. The latter is the predominant mode of acquisition of resistance in clinical settings. The specialized genetic vectors driving HGT in bacteria are known as mobile genetic elements (MGE). The most relevant MGE for the dissemination of AMR are plasmids, which are self-replicating DNA molecules capable of conjugating among different cells, and of transferring several resistance determinants in a single event In REPLAY we have studied how plasmid-mediated antibiotic-resistance evolves in bacteria isolated from human patients. Particularly, we have focused in the plasmid pOXA48 and in the Enterobacteriaceae family of bacteria. pOXA 48 bears a carbapenemase, making that the bacteria that bears this plasmid very difficult to be treated. Carbapenem resistant Enterobacteriaceae are one of the most concerning threats in clinical settings around the world. Resistance to carbapenems, which are considered by the WHO as Critically-Important Antimicrobials, is mainly driven by conjugative plasmids encoding carbapenemases, which are enzymes able to hydrolyse penicillins, cephalosporins, monobactams and carbapenems. Why is REPLAY important for society? As AMR is one of the biggest problems from a sanitary point of view, increasing our understanding of how bacteria become resistant can help us to better treat resistant-infections. Therefore, the ultimate goal of REPLAY is to pave the way to have better and more rationalised treatments to combat the emergence and spread of antibiotic resistances. What are the overall objectives of REPLAY? As plasmid-mediated AMR is arguably the main mechanism of acquisition of AMR in vivo, understanding the evolutionary forces that determine the emergence of plasmid-bacterium associations is urgently needed. The overall goal of REPLAY is to gain an understanding of how plasmid-mediated AMR evolves in clinically relevant bacteria. Mainly, we have focused on understanding the effect of different bacteria from the Enterobacteriaceae family on plasmid-bacterium interactions and compensatory evolution using a range of plasmids and bacterial clones of clinical relevance in a full factorial design.
Data: CORDIS, © European Union
Project objective
Antimicrobial resistance (AMR) in bacteria is one of the main challenges faced by modern medicine and understanding its evolution is urgently required. As any other evolved trait, three fundamental evolutionary forces guide the evolution of AMR: history, chance and selection. The specific role of each force determines whether, by what mechanism, and to what degree AMR evolves in a given population. Horizontal gene transfer is the main route for acquisition of AMR in bacterial pathogens and plasmids play a key role in the spread of resistant determinants. Of critical clinical importance is plasmid-mediated carbapenem-resistance in the Enterobacteriaceae family. The recurrent isolation of certain successful plasmid/bacterium associations in hospitals distributed worldwide is an example of how history and chance constrain the emergence of AMR. For example, pOXA-48 plasmid, encoding the OXA-48 carbapenemase, is frequently associated with the ST11 serotype of Klebsiella in hospitals around the world. Why is pOXA-48 restricted to a handful of clones if it can be mobilized to all K. pneumoniae serotypes? To answer this question, I am proposing a novel project that will analyze the impact of the three evolutionary forces in the evolution of plasmid-mediated AMR in clinical strains of K. pneumoniae. First, using experimental evolution and whole genome sequencing, I will quantitatively analyze the impact of each evolutionary force in AMR evolution. Also, I will study the adaptive mutational pathways leading to the compensation of plasmid-mediated costs. Then, I will use the novel high-throughput genetic screen CRISPRi, which allows silencing the expression of all chromosomal and plasmid genes one by one, to analyze the molecular basis determining the successful plasmid/bacterium associations. Altogether this cutting-edge proposal will greatly impact our ability to predict AMR evolution, paving the way for the development new intervention strategies to counteract AMR.
Original text from CORDIS.
Participants
- FUNDACION PARA LA INVESTIGACION BIOMEDICA DEL HOSPITAL UNIVERSITARIO RAMON Y CAJAL · MadridCoordinatorSpain
Links
Data: CORDIS, © European Union